Cushing’s SyndromeCushing’s Syndrome

Jason McCluneJason McClune

AM ReportAM Report

2/6/20082/6/2008

• This patient had Ectopic ACTH Syndrome

• Non-pituitary tumor secreting either ACTH or CRH causing bilateral adrenal hyperplasia

• excess CRH or ACTH is indistinguishable

Cushing’s=hypercortisolismCushing’s=hypercortisolism

Cushing's Syndrome-Cushing's Syndrome- Clinical Clinical effects of increased glucocorticoid effects of increased glucocorticoid hormone- all causes or excess hormone- all causes or excess cortisolcortisol

Cushing's Disease-Cushing's Disease- ACTH ACTH producing pituitary adenomaproducing pituitary adenoma

POMC (proopiomelanocortin gene) POMC (proopiomelanocortin gene) which codes for ACTH, MSH which codes for ACTH, MSH (melanocyte stimulating hormone), (melanocyte stimulating hormone), Beta lipotropin, Beta endorphin, Beta lipotropin, Beta endorphin, metenkephalin. metenkephalin.

POMC is induced by CRH (rarely tumors POMC is induced by CRH (rarely tumors can make CRH causing Cushing's) and can make CRH causing Cushing's) and suppressed by glucocorticoids. suppressed by glucocorticoids.

Symptoms of Excess CortisolSymptoms of Excess Cortisol Truncal obesityTruncal obesity Moon faceMoon face Fat deposits supraclavicular Fat deposits supraclavicular

fossa and posterior neck- fossa and posterior neck- buffalo humpbuffalo hump

HTNHTN HirsutismHirsutism Amenorrhea or impotenceAmenorrhea or impotence DepressionDepression Thin skinThin skin Easy bruisingEasy bruising Purplish abdominal striaePurplish abdominal striae Proximal muscle weaknessProximal muscle weakness OsteoporosisOsteoporosis Diabetes MellitusDiabetes Mellitus Avascular necrosisAvascular necrosis Wound healing impairedWound healing impaired Pysch symptomsPysch symptoms HyperpigmentationHyperpigmentation Hypokalemic alkalosisHypokalemic alkalosis

Ectopic ACTHEctopic ACTH

All the previous symptoms but…..All the previous symptoms but….. Ectopic dominated by :Ectopic dominated by :

Hypokalemic alkalosis (dominant feature)Hypokalemic alkalosis (dominant feature) Fluid retentionFluid retention HTNHTN Glucose intoleranceGlucose intolerance Steroid psychosisSteroid psychosis

Absence of other features may be Absence of other features may be explained by more sudden onset by explained by more sudden onset by acquired ACTH from tumor.acquired ACTH from tumor.

HypokalemiaHypokalemia

Excess mineralocorticoids produced by ACTH Excess mineralocorticoids produced by ACTH stimulation of adrenal gland, leads to high stimulation of adrenal gland, leads to high levels of cortisol activity through levels of cortisol activity through aldosterone and the mineralocorticoid aldosterone and the mineralocorticoid receptor leading to severe hypokalemia by receptor leading to severe hypokalemia by activation of the Na/K ATPase pump on the activation of the Na/K ATPase pump on the basolateral membrane.basolateral membrane.

For the rest of us that means……For the rest of us that means……

Retain Na, and loose K in the cortical collecting duct

Causes of Cushing Causes of Cushing SyndromeSyndrome

IatrogenicIatrogenic ACTH secreting pituitary microadenoma (ACTH secreting pituitary microadenoma (Cushing’s Cushing’s

diseasedisease)- )- 48% cases of Cushing’s syndrome 48% cases of Cushing’s syndrome 3 x more women than men3 x more women than men 15% of pituitary tumors (usu 315% of pituitary tumors (usu 3rdrd or 4 or 4thth decade of life) decade of life)

Adrenal tumors-Adrenal tumors- 32%, usu unilateral 32%, usu unilateral general rule: general rule: Small- benign, mostly cortisolSmall- benign, mostly cortisol large- carcinoma, cortisol and androgenslarge- carcinoma, cortisol and androgens

Ectopic ACTH secretion-Ectopic ACTH secretion- ie neoplasms (10%)- most ie neoplasms (10%)- most common small cell lung CA common small cell lung CA

15%- cause not identified15%- cause not identified

Ectopic ACTHEctopic ACTH

SCLC >50%SCLC >50% Thymic carcinoid 15%Thymic carcinoid 15% Islet cell tumors 10%Islet cell tumors 10% Bronchial carcinoid 10%Bronchial carcinoid 10% Other carcinoids 5%Other carcinoids 5% Pheochromocytomas 2%Pheochromocytomas 2%

Differential DiagnosisDifferential Diagnosis

AlcoholismAlcoholism Anorexia nervosa (high urine free Anorexia nervosa (high urine free

cortisol)cortisol) Familial cortisol resistanceFamilial cortisol resistance Familial partial lipodystrophy type IFamilial partial lipodystrophy type I HAART may mimic Cushing’s HAART may mimic Cushing’s

clinically but not diagnostically.clinically but not diagnostically.

Complications of Cushing's if Complications of Cushing's if UntreatedUntreated

DiabetesDiabetes HTNHTN Osteoporotic fractures and avascular Osteoporotic fractures and avascular

necrosisnecrosis InfectionsInfections NephrolithiasisNephrolithiasis PsychosisPsychosis

Screening TestScreening Test

Overnight dexamethasone Overnight dexamethasone suppression testsuppression test (1 mg at 11 pm, (1 mg at 11 pm, cortisol measured at 8 am) – normal cortisol measured at 8 am) – normal <2 micrograms/dL<2 micrograms/dL

OrOr 24 hour urine free cortisol (>140 24 hour urine free cortisol (>140

nmol/day)nmol/day)

Other Test That May be Other Test That May be UsefulUseful

Midnight serum cortisol >7.5 Midnight serum cortisol >7.5 micrograms/dL (same time zone for 3 micrograms/dL (same time zone for 3 days, NPO for 3 hours)days, NPO for 3 hours)

Midnight saliva cortisol >550 Midnight saliva cortisol >550 nanograms/dL, 93% sensitivenanograms/dL, 93% sensitive

False PositivesFalse Positives

Severe depressionSevere depression Severe stressSevere stress Phenytoin/phenobarbital/rifampin Phenytoin/phenobarbital/rifampin

(accelerated metabolism of dex)(accelerated metabolism of dex) Estrogen (pregnancy or OCP)Estrogen (pregnancy or OCP) Morbid obesityMorbid obesity

Confirmatory TestConfirmatory Test

Low dose dexamethasone suppression testLow dose dexamethasone suppression test Dexamethasone 0.5 mg q 6 x 48 hoursDexamethasone 0.5 mg q 6 x 48 hours Measure urine cortisol during the last 24 Measure urine cortisol during the last 24

hours (urine free cortisol >20 hours (urine free cortisol >20 micrograms/dL or urine 17-micrograms/dL or urine 17-hydroxycorticosteroid >4.5 mg/d)hydroxycorticosteroid >4.5 mg/d)

OrOr plasma cortisol (failure to fall to <5 plasma cortisol (failure to fall to <5

micrograms/dL)micrograms/dL)

Pituitary Tumor vs. EctopicPituitary Tumor vs. Ectopic

ACTH levels may distinguish: ACTH levels may distinguish: ACTH independent (adrenal or exogenous ACTH independent (adrenal or exogenous

glucocorticoids) glucocorticoids) from from ACTH dependent (pituitary, ectopic ACTH) ACTH dependent (pituitary, ectopic ACTH)

ACTH independent- low or undetectable ACTH independent- low or undetectable ACTHACTH

ACTH dependent-ACTH elevatedACTH dependent-ACTH elevated In addition ectopic ACTH levels are usu 8x In addition ectopic ACTH levels are usu 8x

higher than pituitary caused ACTH higher than pituitary caused ACTH secreting adenomassecreting adenomas

TreatmentTreatment

Cushing’s DiseaseCushing’s Disease: Transphenoidal : Transphenoidal resection of pituitary adenomaresection of pituitary adenoma

Adrenal neoplasmsAdrenal neoplasms: resection: resection Ectopic ACTHEctopic ACTH: resection if possible: resection if possible Bilateral adrenal hyperplasiaBilateral adrenal hyperplasia: may : may

need adrenalectomies (lifelong need adrenalectomies (lifelong glucocorticoid and mineralcorticoid glucocorticoid and mineralcorticoid replacement)replacement)

‘‘Medical’ AdrenalectomyMedical’ Adrenalectomy

Medications that inhibit steroidogenesisMedications that inhibit steroidogenesis Ketoconazole (600 to 1200 mg/day)Ketoconazole (600 to 1200 mg/day) metyrapone (exacerbates female metyrapone (exacerbates female

virilization) (2-3 g/day)virilization) (2-3 g/day) Mitotane(2-3 G/day)- slow onsetMitotane(2-3 G/day)- slow onset Aminoglutethinide (1g/day)Aminoglutethinide (1g/day) Ocreotide can work in 1/3 of patients.Ocreotide can work in 1/3 of patients.Major side affect is adrenal insufficiency, Major side affect is adrenal insufficiency,

therefore start at lowest dose and titratetherefore start at lowest dose and titrate

PrognosisPrognosis

Benign adrenal adenoma- 95% 5 year Benign adrenal adenoma- 95% 5 year survival, 90% 10 yearsurvival, 90% 10 year

Cushing’s disease (pituitary adenoma) same Cushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal survival, but 10-20% transphenoidal resection failure rate over 10 years. resection failure rate over 10 years.

Ectopic ACTH survival depends on Ectopic ACTH survival depends on malignancymalignancy

Unknown cause of elevated ACTH- 65% 5 Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survivalyear survival, 55% 10 year survival

Adrenal carcinoma- median survival 7 monthsAdrenal carcinoma- median survival 7 months